RESUMO
Metabolic syndrome (MetS) is a term used to characterize individuals having at least three of the following diseases: obesity, dyslipidemia, hyperglycemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease (NAFLD). It is widespread, and the number of individuals with MetS is increasing. However, the events leading to the manifestation of MetS are not well-understood. Here, we show that loss of murine ARV1 (mARV1) results in resistance to acquiring diseases associated with MetS. Arv1-/- animals fed a high-fat diet were resistant to diet-induced obesity, had lower blood cholesterol and triglyceride levels, and retained glucose tolerance and insulin sensitivity. Livers showed no gross morphological changes, contained lower levels of cholesterol, triglycerides, and fatty acids, and showed fewer signs of NAFLD. Knockout animals had elevated levels of liver farnesol X receptor (FXR) protein and its target, small heterodimer protein (SHP). They also had decreased levels of CYP7α1, CYP8ß1, and mature SREBP1 protein, evidence suggesting that liver FXR signaling was activated. Strengthening this hypothesis was the fact that peroxisome proliferator-activating receptor α (PPARα) protein was elevated, along with its target, fibroblast growth factor 21 (FGF21). Arv1-/- animals excreted more fecal cholesterol, free fatty acids, and bile acids. Their small intestines had 1) changes in bile acid composition, 2) an increase in the level of the intestinal FXR antagonist, tauromuricholic acid, and 3) showed signs of attenuated FXR signaling. Overall, we believe that ARV1 function is deleterious when consuming a high-fat diet. We further hypothesize that ARV1 is critical for initiating events required for the progression of diseases associated with MetS and NAFLD.
Assuntos
Proteínas de Transporte/genética , Deleção de Genes , Proteínas de Membrana/genética , Síndrome Metabólica/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Animais , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/patologia , Triglicerídeos/sangueRESUMO
C-terminal Src kinase (Csk) is one of the critical negative regulators of the Src family of kinases. The Src family of kinases are nonreceptor tyrosine kinases that regulate inflammation, cell proliferation, motility, and adhesion. To investigate potential histologic lesions associated with systemic loss of Csk gene activity in adult mice, conditional Csk-knockout mice were examined. Cre-mediated systemic excision of Csk induced by tamoxifen treatment resulted in multiorgan inflammation. Specifically, induction of Csk gene excision with three days of tamoxifen treatment resulted in greater than 90% gene excision. Strikingly, these mice developed enteritis that ranged from minimal and suppurative to severe, fibrinonecrosuppurative and hemorrhagic. Other inflammatory lesions included suppurative pneumonia, gastritis, and myocarditis, and increased numbers of inflammatory cells within the hepatic parenchyma. When tamoxifen treatment was reduced from three days to one day in an effort to lower the level of Csk gene excision and limit lesion development, the mice developed severe suppurative to pyogranulomatous pneumonia and minimal to mild suppurative enteritis. Lesions observed secondary to Csk gene excision suggest important roles for Csk in downregulating the proinflammatory activity of the Src family of kinases and limiting neutrophil-mediated inflammation.
Assuntos
Inflamação/veterinária , Camundongos Knockout/metabolismo , Supuração/veterinária , Quinases da Família src/metabolismo , Animais , Southern Blotting , Proteína Tirosina Quinase CSK , Feminino , Expressão Gênica , Inflamação/metabolismo , Inflamação/patologia , Masculino , Supuração/metabolismo , Supuração/patologiaRESUMO
Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth. Thus, discovery of more potent PME-1 inhibitors may be beneficial for the treatment of endometrial cancer.
Assuntos
Adenocarcinoma/terapia , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Neoplasias do Endométrio/terapia , Serotonina/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Animais , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/genética , Feminino , Humanos , Imuno-Histoquímica , Camundongos SCID , Invasividade Neoplásica , Fenótipo , Interferência de RNA , Terapêutica com RNAi/métodos , Serotonina/farmacologiaRESUMO
Endometriosis is a chronic, hormone-dependent, inflammatory disease, characterized by the presence and growth of endometrial tissue outside the uterine cavity. It is associated with moderate to severe pelvic and abdominal pain symptoms, subfertility and a marked reduction in health-related quality of life. Furthermore, relevant co-morbidities with affective disorders like depression or anxiety have been described. These conditions have a worsening effect on pain perception in patients and might explain the negative impact on quality of life observed in those suffering from endometriosis-associated pain. Whereas several studies using rodent models of endometriosis focused on biological and histopathological similarities with the human situation, the behavioral characterization of these models was never performed. This study investigated the anxiety-related behaviors in a syngeneic model of endometriosis. Using elevated plus maze and the novel environment induced feeding suppression assays we observed the presence of anxiety-related behaviors in endometriosis-induced mice. In contrast, locomotion or generalized pain did not differ between groups. These results indicate that the presence of endometriosis lesions in the abdominal cavity could, similarly to patients, induce profound psychopathological changes/impairments in mice. These readouts might provide additional tools for preclinical identification of mechanisms relevant for development of endometriosis-related symptoms.
RESUMO
BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFalpha (hTNFalpha) have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFalpha transgenic mouse line. RESULTS: In addition to arthritis, these hTNFalpha transgenic mice demonstrated major alterations in body composition, metabolic rate, leptin levels, response to a high-fat diet, bone mineral density and content, impaired fertility and male sexual function. Many phenotypes displayed an earlier onset and a higher degree of severity in males, pointing towards a significant degree of sexual dimorphism in response to deregulated expression of TNFalpha. CONCLUSION: These results highlight the potential usefulness of this transgenic model as a resource for studying the progressive effects of constitutively expressed low levels of circulating TNFalpha, a condition mimicking that observed in a number of human pathological conditions.
Assuntos
Modelos Animais de Doenças , Camundongos Transgênicos , Fenótipo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Animais , Feminino , Expressão Gênica , Masculino , CamundongosRESUMO
Our approach has been to power studies to allow for detection of at least modest changes from a wild-type littermate control, include assays with overlapping physiological systems to provide cross-functional interpretive value, and to employ challenge assays.